crossing96/oncoscreening huggingface dataset:
Lymphotoxin β receptor activation promotes bladder cancer in a nuclear factor-κB-dependent manner.	Bladder cancer (BCa) is the most common tumor of the urinary system. Chronic inflammation in the papillary urothelial neoplasm of low malignant potential (PUNLMP)may contribute to carcinogenesis, including that of BCa, via poorly understood mechanisms. In this study, we show that the lymphotoxin β receptor (LTβR) is upregulated in BCa via activation of the canonical and non-canonical nuclear factor-κB (NF-κB) pathways. The mRNA expression of LTβR in 81 BCa, 10 chronic cystitis and 23 healthy bladder mucosa tissues was investigated by reverse transcription-fluorescent quantitative polymerase chain reaction (RT-FQ-PCR), and protein expression was studied in 73 BCa, 30 cystitis and 15 healthy parafﬁn-embedded tissue sections by immunohistochemistry. Both LTβR mRNA and protein were upregulated in BCa and cystitis compared to the healthy group (P<0.05). The mRNA level of the downstream NF-κB canonical pathway p65 gene and of the non-canonical pathway RelB gene were higher in the BCa and cystitis groups compared to the healthy one. The level of phosphorylated p65 (p-p65) protein of the canonical NF-κB pathway and that of p52, a protein of the non-canonical NF-κB pathway, were also higher in the BCa and cystitis group compared to the healthy group. The levels of these proteins significantly correlated to the pathological grade, clinical stage and lymph node metastasis of BCa patients (P<0.05). In addition, there was a positive correlation between LTβR and NF-κB pathway proteins. Thus, LTβR signaling may be involved in promoting BCa through the NF-κB pathway, and which may represent the molecular link between inflammation and BCa.	bladder
miR-200c inhibits invasion, migration and proliferation of bladder cancer cells through down-regulation of BMI-1 and E2F3.	BACKGROUND: MicroRNA-200c (miR-200c) is one of the short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression. It also acts as considerable modulator in the process of epithelial-to-mesenchymal transition (EMT), a cell development regulating process that affects tumor development and metastasis. However, the role of miR-200c in bladder cancer cells and its mechanism has not been well studied. The purpose of this study was to determine the potential role of miR-200c in regulating EMT and how it contributed to bladder cancer cells in invasion, migration and proliferation. METHODS: Real-time reverse transcription-PCR was used to identify and validate the differential expression of MiR-200c involved in EMT in 4 bladder cancer cell lines and clinical specimens. A list of potential miR-200 direct targets was identified through the TargetScan database. The precursor of miR-200c was over-expressed in UMUC-3 and T24 cells using a lentivirus construct, respectively. Protein expression and signaling pathway modulation were validated through Western blot analysis and confocal microscopy, whereas BMI-1 and E2F3, direct target of miR-200c, were validated by using the wild-type and mutant 3'-untranslated region BMI-1/E2F3 luciferase reporters. RESULTS: We demonstrate that MiR-200c is down-regulated in bladder cancer specimens compared with adjacent ones in the same patient. Luciferase assays showed that the direct down-regulation of BMI-1 and E2F3 were miR-200c-dependent because mutations in the two putative miR-200c-binding sites have rescued the inhibitory effect. Over-expression of miR-200c in bladder cancer cells resulted in significantly decreased the capacities of cell invasion, migration and proliferation. miR-200c over-expression resulted in conspicuous down-regulation of BMI-1 and E2F3 expression and in a concomitant increase in E-cadherin levels. CONCLUSIONS: miR-200c appears to control the EMT process through BMI-1 in bladder cancer cells, and it inhibits their proliferation through down-regulating E2F3. The targets of miR-200c include BMI-1 and E2F3, which are a novel regulator of EMT and a regulator of proliferation, respectively.	bladder
Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.	PURPOSE: Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies. PATIENTS AND METHODS: Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method. RESULTS: The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively. CONCLUSION: This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.	bladder
Diabetes mellitus with poor glycemic control increases bladder cancer recurrence risk in patients with upper urinary tract urothelial carcinoma.	BACKGROUND: The association of diabetes mellitus and bladder cancer recurrence following radical nephroureterectomies (RNUs) in patients with upper urinary tract urothelial carcinoma (UTUC) was investigated. METHODS: Between January 1996 and March 2009, 538 patients with UTUC who received RNU and had no previous bladder cancer histories were enrolled. The clinicopathological characteristics were obtained and used for the analysis of metachronous bladder recurrence by using Cox proportional hazard model. RESULTS: The diabetic patients (N = 104, 19.3%) were elderly (72 vs 67 years, p < 0.001) and had more hypertension (56.7 vs 34.5%, p < 0.001) as compared with non-diabetic patients. There was no significant difference in the rest of clinicopathological characteristics between patient groups. During the median follow-up duration of 51 months, bladder recurrences were discovered in 47.1 and 33.1% of diabetic and non-diabetic patients with UTUC, respectively. Poorly controlled diabetic patients (HbA1c ≥ 7.0%) exhibited a shorter duration of bladder cancer recurrence-free survival as compared with those with good glycemic controlled diabetes mellitus and without diabetes mellitus (log-rank test, p < 0.001 and <0.001, respectively). In the multivariate analysis, male gender [hazard ratio (HR) = 1.67, p = 0.017], ureteral tumour (HR = 1.61, p = 0.020), end-stage renal disease (HR = 2.09, p = 0.030) and diabetes mellitus with poor glycemic control (HR = 2.10, p < 0.018) independently predicted bladder recurrence after RNU. CONCLUSIONS: Diabetes mellitus with poor glycemic control (HbA1c  ≥ 7.0%) increases the risk of subsequent bladder cancer recurrence. These results underscore the need for intensive glycemic control and close follow-up for diabetic patients.	bladder
Predictors of outcome in bladder cancer.	Tumor stage and grade have largely been responsible for directing treatment algorithms in bladder cancer. However, the considerable heterogeneity of tumor biology in bladder cancer is incompletely characterized by stage and grade alone, and recent efforts to improve predictive models in bladder cancer may significantly improve accuracy and calibration. This article addresses how current nomograms and risk tables may be best used to individualize bladder cancer management.	bladder
Prognostic value of serum nicotinamide phosphoribosyltransferase in patients with bladder cancer.	AIM: To analyze the serum nicotinamide phosphoribosyltransferase (Nampt) level and its prognostic value in bladder cancer (BC). METHODS: The study included 131 patients with transitional cell BC and 109 healthy controls from the West China Hospital of Sichuan University in the period between 2007 and 2013. Nampt concentration in serum was measured by commercial ELISA kits for human Nampt. RESULTS: The serum Nampt protein level in patients with BC (mean ± standard deviation, 16.02 ± 7.95 ng/mL) was significantly higher than in the control group (6.46 ± 2.08 ng/mL) (P < 0.001). Serum Nampt level was an independent prognostic marker of non-muscle-invasive BC, with a higher serum Nampt level (>14.74 ng/mL) indicating shorter recurrence-free survival rate (hazard ratio=2.85, 95% confidence interval, 1.01-8.06; P=0.048). CONCLUSION: Our results suggest that serum Nampt level may serve as a biomarker of BC and an independent prognostic marker of non-muscle-invasive BC.	bladder
Endoscopic molecular imaging of human bladder cancer using a CD47 antibody.	A combination of optical imaging technologies with cancer-specific molecular imaging agents is a potentially powerful strategy to improve cancer detection and enable image-guided surgery. Bladder cancer is primarily managed endoscopically by white light cystoscopy with suboptimal diagnostic accuracy. Emerging optical imaging technologies hold great potential for improved diagnostic accuracy but lack imaging agents for molecular specificity. Using fluorescently labeled CD47 antibody (anti-CD47) as molecular imaging agent, we demonstrated consistent identification of bladder cancer with clinical grade fluorescence imaging systems, confocal endomicroscopy, and blue light cystoscopy in fresh surgically removed human bladders. With blue light cystoscopy, the sensitivity and specificity for CD47-targeted imaging were 82.9 and 90.5%, respectively. We detected variants of bladder cancers, which are diagnostic challenges, including carcinoma in situ, residual carcinoma in tumor resection bed, recurrent carcinoma following prior intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), and excluded cancer from benign but suspicious-appearing mucosa. CD47-targeted molecular imaging could improve diagnosis and resection thoroughness for bladder cancer.	bladder
Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy.	BACKGROUND: Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response. METHODS: Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation. RESULTS: Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.	bladder
MiR-124 retards bladder cancer growth by directly targeting CDK4.	MicroRNAs (miRNAs) are a class of non-coding small RNAs that act as negative regulators of gene expression by binding to the 3'-untranslated region (3'UTR) of target mRNAs. In order to investigate the physiological role of miR-124 in bladder cancer, target genes of miR-124 were predicted by the TargetScan software, and cyclin-dependent kinase (CDK4), which has been implicated as a regulator of cell cycle, was chosen for further study. MiR-124 could significantly repress CDK4 expression by targeting its binding site in the 3'UTR of CDK4 in vitro. In both bladder cancer cell lines and tissues, the expression of miR-124 was significantly down-regulated, while CDK4 expression was up-regulated. Ectopic expression of miR-124 in transplanted HT1197 cells resulted in the retardation of tumor growth in mouse tumor xenografts. And the expression of miR-124 and CDK4 showed an obvious inverse correlation in these xenograft tissues, which was also observed in human bladder cancer tissue samples. Taken together, our results strongly suggest that miR-124 can arrest cell cycle and restrain the growth of bladder cancer by targeting CDK4 directly.	bladder
Squamous carcinoma of the ovary.	Squamous ovarian cancer (SOC) represents a (very) rare subtype of ovarian cancer. The lack of evidence on which to base management presents significant challenges. The small number of patients prohibits randomised studies to establish level 1 evidence, and no non-randomised studies or prospective series have been reported. Here, we present a review of the available literature on squamous ovarian cancer and explore some lessons learnt from squamous cancers originating from other primary sites to see if these can be applied to SOC.	bladder
Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract after failure of one platinum-based systemic therapy in clinical practice.	BACKGROUND: Patients with transitional cell carcinoma of the urothelial tract (TCCU) who fail initial platinum-based chemotherapy for advanced disease represent a challenge in daily clinical practice. Vinflunine is approved by the European Medicine Agency (EMA) but, up to now, limited experience has been reported outside clinical trials. METHODS: We assessed the efficacy and safety of vinflunine in an unselected group of 102 consecutive patients with metastatic TCCU. RESULTS: The median age was 67 years (range 45-83). Among the most common comorbidities that patients presented at baseline were hypertension (50.5%) and diabetes (20.7%).Distant metastases were present in retroperitoneal nodes (58%), lung (29.3%), and bone (20.2%). The ECOG 0, 1 and 2 performance status at the start of vinflunine were 31.3%, 60.6% and 8.1%, respectively. The most commonly reported adverse events of any grade were constipation 70.6% (5.9% grade 3-4), vomiting 49.1% (2% grade 3-4), neutropenia 48.1% (12.8% grade 3-4) and abdominal pain 34.3% (4.9% grade 3-4). A median of 4 cycles of vinflunine was administered per patient (range 1-18). Median progression free and overall survival for all patients (N = 102) were 3.9 months (2.3-5.5) and 10 months (7.3-12.8), respectively. Time to tumor progression was 4.3 months (2.6-5.9). Two patients (2%) achieved CR, 23 (22.5%) patients had PR, and 42 (41.2%) presented SD as best response. The clinical benefit rate with vinflunine was 65.7%. CONCLUSIONS: Our results show that the behavior of vinflunine in routine clinical practice resembles that of the pivotal phase III randomized study.	bladder
Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment.	Adenosine A(2A) receptor (A(2A)R) blockade enhances innate and adaptive immune responses. However, mouse genetic studies have shown that A(2A)R deletion does not inhibit the growth of all tumor types. In the current study, we showed that growth rates for ectopic melanoma and bladder tumors are increased in Adora2a(-/-) mice within 2 weeks of tumor inoculation. A(2A)R deletion in the host reduced numbers of CD8(+) T cells and effector-memory differentiation of all T cells. To examine intrinsic functions in T cells, we generated mice harboring a T-cell-specific deletion of A(2A)R. In this host strain, tumor-bearing mice displayed increased growth of ectopic melanomas, decreased numbers of tumor-associated T cells, reduced effector-memory differentiation, and reduced antiapoptotic IL7Rα (CD127) expression on antigen-experienced cells. Intratumoral pharmacologic blockade similarly reduced CD8(+) T-cell density within tumors in wild-type hosts. We found that A(2A)R-proficient CD8(+) T cells specific for melanoma cells displayed a relative survival advantage in tumors. Thus, abrogating A(2A)R signaling appeared to reduce IL7R expression, survival, and differentiation of T cells in the tumor microenvironment. One implication of these results is that the antitumor effects of A(2A)R blockade that can be mediated by activation of cytotoxic T cells may be overcome in some tumor microenvironments as a result of impaired T-cell maintenance and effector-memory differentiation. Thus, our findings imply that the efficacious application of A(2A)R inhibitors for cancer immunotherapy may require careful dose optimization to prevent activation-induced T-cell death in tumors.	bladder
Correlation of ANXA1 expression with drug resistance and relapse in bladder cancer.	OBJECTIVE: To investigate the expression of annexin a1 (ANXA1) in adriamycin-resistant human bladder cancer cell line (pumc-91/ADM) compared with the parental cell line (pumc-91) and its relevance to the drug resistance of bladder cancer, as well as explore the relevance of ANXA1 in recurrent bladder cancer tissues as pertinent to relapse. METHODS: qRT-PCR and Western blot were implemented to research the level of ANXA1 in two cell lines (pumc-91/ADM and pumc-91). Immunohistochemistry was applied to explore ANXA1 expression in bladder cancer tissues of different intervals of relapse. The association of ANXA1 with clinicopathological parameters was analyzed. RESULTS: The expression of ANXA1 was downregulated in drug-resistant cell line pumc-91/ADM compared to pumc-91. The bladder cancer tissues recurring two years later exhibited higher ANXA1 levels. ANXA1 expression level was positively correlated with T stage, while it was not connected with histological grade strongly. The expression level and influencing factors of ANXA1 in recurrent tissues of bladder cancer were clarified for the first time. CONCLUSION: ANXA1 may become a promising marker to predict the recurrence and drug resistance of bladder cancer and provide guidance for surveillance.	bladder
First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors.	PURPOSE: AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population. EXPERIMENTAL DESIGN: Standard 3+3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies. RESULTS: Sixty-two patients were treated with doses ranging from 10 to 120 mg/m(2) twice weekly and 150 to 310 mg/m(2) once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m(2), which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m(2) as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients. CONCLUSION: AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.	bladder
MicroRNA-137 upregulation increases bladder cancer cell proliferation and invasion by targeting PAQR3.	There is increasing evidence suggesting that dysregulation of some microRNAs (miRNAs) may contribute to tumor progression and metastasis and have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Previous studies have shown that miR-137 is dysregulated in some malignancies, but its role in bladder cancer is still unknown. In our study, we find that miR-137 is up-regulated in human bladder cancer tissues and cell lines. Moreover, the higher level of miR-137 was associated with pM or pTNM stage in clinical bladder cancer patients. Enforced expression of miR-137 in bladder cancer cells significantly enhanced their proliferation, migration and invasion. Bioinformatics analysis identified the tumor suppressor gene PAQR3 as a potential miR-137 target gene. Further studies indicated that miR-137 suppressed the expression of PAQR3 by binding to its 3'-untranslated region. Silencing of PAQR3 by small interfering RNAs phenocopied the effects of miR-137 overexpression, whereas restoration of PAQR3 in bladder cancer cells bladder cancer cells overexpressing miR-137, partially reversed the suppressive effects of miR-137. These findings indicate that miR-137 could be a potential oncogene in bladder cancer.	bladder